Stereoselective synthesis of cis- and trans-2,3-disubstituted eight-membered medium-ring ethers based on Ireland-Claisen rearrangement of 3-alkoxy-2-propenyl glycolate esters and ring-closing olefin metathesis

Article abstract of DOI:10.1016/j.tetlet.2005.03.114

A simple stereoselective synthesis of cis- and trans-2,3-disubstituted medium-sized cyclic ethers has been developed based on geometry-selective synthesis of 3-alkoxy-2-propenyl glycolate esters, Ireland-Claisen rearrangement of the glycolate esters, and ring-closing olefin metathesis.

Full text of DOI:10.1016/j.tetlet.2005.03.114

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3465–3468
Stereoselective synthesis of cis- and trans-2,3-disubstituted
eight-membered medium-ring ethers based on Ireland–Claisen
rearrangement of 3-alkoxy-2-propenyl glycolate esters
and ring-closing olefin metathesis
Kenshu Fujiwara,* Akiyoshi Goto, Daisuke Sato, Hidetoshi Kawai and Takanori Suzuki
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 15 February 2005; revised 15 March 2005; accepted 17 March 2005
Available online 5 April 2005
Abstract—A simple stereoselective synthesis of cis- and trans-2,3-disubstituted medium-sized cyclic ethers has been developed based
on geometry-selective synthesis of 3-alkoxy-2-propenyl glycolate esters, Ireland–Claisen rearrangement of the glycolate esters, and
ring-closing olefin metathesis.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Medium-ring ethers have attracted significant synthetic
attention, because they are often seen in potent bioactive
natural products,1 such as ciguatoxin.2 Among the many
methods available for their synthesis,3 a ring-closing
olefin metathesis reaction (RCM) has now interested
synthetic chemists, since it realizes efficient ring-closure
under mild catalytic conditions and tolerates a wide
variety of functional groups in its substrates.4 On the
other hand, the diene substrates of RCM for the synthe-
sis of medium-ring ethers, which include an acyclic
branched ether part, are still difficult to prepare. There-
fore, stereoselective construction of these acyclic
branched ethers has been a current crucial challenge in
synthetic chemistry.5 In this context, we have studied
an application of Ireland–Claisen rearrangement6 to
the synthesis of branched ethers. Here, a simple stereo-
selective synthesis of medium-ring ethers based on the
Ireland–Claisen rearrangement of 3-alkoxy-2-propenyl
glycolates followed by RCM is described.6d,e
Ring-Closing
Olefin
Metathesis
5
4
4
3
R1
R2
CO2Me
R1
R2
3
8
1
O
2
2
O
1
CO2Me
1a: R1=OR, R2=H
2a: R1=OR, R2=H
1b: R1=H, R2=OR
2b: R1=H, R2=OR
Ireland-Claisen
Rearrangement
R1
R1
R2
R2
O
O
O
O
R3Si
O
O
4a: R1=OR, R2=H
3a: R1=OR, R2=H
4b: R1=H, R2=OR
3b: R1=H, R2=OR
Scheme 1.
Our strategy for stereoselective synthesis of medium-
ring ethers was represented by the retrosynthetic scheme
of cis- and trans-3-alkoxy-2-carbomethoxy-2,3,6,7-tetra-
hydrooxocines (1a and 1b) shown in Scheme 1, where
Ireland–Claisen rearrangement6 of 3-alkoxy-2-propenyl
glycolate ester 47 into 2,3-dialkoxy-4-pentenoate ester
2 and the subsequent RCM of 2 into 1 were the key
steps. Since it was reported that a glycolate ester could
be facilely transformed into a Z-ketene silyl acetal under
the Ireland–Claisen conditions,7a–e Z-ketene silyl acetal
3 was thought to mediate the rearrangement of 4 into
2. The stereochemistry of 2 could be predicted from
the presumed chair-type conformation of 3 in the tran-
sition state.6 Namely, E-3-alkoxy-2-propenyl derivative
*
Corresponding author. Tel.: +81 11 706 2701; fax: +81 11 706
4924; e-mail: fjwkn@sci.hokudai.ac.jp
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.114

3466
K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 3465–3468
CO2Me
PMPO
CO2Me
a
b
OH
OH
O
BnO
BnO
a or b
Me Me
c
HO
O
5
6
7
8
9
PMPO
PMPO
O
O
13
15
16
c
d, e
O
N
S
BnO
O
CO2H
O
14
O
O
O
OPMP
OPMP
CO2R
H
9
10
3
CO2Me
f
4
d
2
NOE
OBn
H
1O
4 H
OBn
O
2
CO2Me
8
3
CO2Me
JH2-H3 = 9.2 Hz
f
17: R = H
18: R = Me
19
H
e
1O
O
8
JH2-H3 = 3.3 Hz
11
12
Scheme 3. Reagents and conditions: (a) s-BuLi, TMEDA, THF,
ꢀ78 ꢁC, 1 h, then MoOPH, ꢀ78 ꢁC, 1 h, then 25 ꢁC, 30 min, 23%; (b)
s-BuLi, TMEDA, THF, ꢀ78 ꢁ C, 1 h, then 14, ꢀ78!25 ꢁC, 30 min,
29%; (c) 9 (2.7 equiv), EDCIÆHCl, DMAP, CH2Cl2, 25 ꢁC, 2 h; (d)
KHMDS, TMSCl, THF, ꢀ78!25 ꢁC, 1 h, 81% from 15; (e) CH2N2,
THF–Et2O, 0 ꢁC, 20 min, 81%; (f) (H2IMes)(PCy3)Cl2RuCHPh (0.1
equiv), CH2Cl2, reflux, 5.5 h, 53%. PMP: 4-methoxyphenyl.
Scheme 2. Reagents and conditions: (a) Me3P, CH2Cl2, 0 ꢁC, 30 min,
96%; (b) DIBAH, CH2Cl2, ꢀ78 ꢁC, 1 h, 93%; (c) DCC, DMAP,
CH2Cl2, 8 (0.83 equiv), 0!23 ꢁC, 93% from 8; (d) KHMDS, THF,
ꢀ78 ꢁC, 1 min, then TMSCl, ꢀ78!23 ꢁC, 35 min; (e) CH2N2, THF–
Et2O, 23 ꢁC, 1 min, 79% from 10; (f) (PCy3)2Cl2RuCHPh (0.1 equiv),
CH2Cl2, reflux, 6.5 h, 87%.
deprotonation–oxygenation process starting from an
allyl ether. Deprotonation of allyl ether 13 with s-BuLi
in the presence of TMEDA followed by treatment with
MoOPH13 gave the desired Z-type alcohol 15 as the sole
geometrical isomer in 23% yield. From the fact of signif-
icant byproduction of 4-methoxyphenol, the modest
yield of 15 was thought to result from decomposition
of 13 caused by the oxygenation at the carbon adjacent
to the PMPO group. In order to suppress the undesired
oxygenation, Davisꢀ reagent 1414 was then employed as
a bulky oxidant that would improve the desired regiose-
lectivity by its steric hindrance. The reaction was carried
out in a similar way and produced 15 as the sole geomet-
rical isomer in 29% yield. In this case, the byproduction
of 4-methoxyphenol was reduced, but a significant
amount of 4-methoxyphenyl-1-propenyl ether was
given.15 Although the problem of the modest yield
remained to be solved, geometrically pure 15 was simply
obtained. Treatment of 15 and 9 with EDCIÆHCl
followed by extractive workup gave almost pure ester
16.
4a would give syn-2,3-dialkoxide 2a via 3a, and Z-deriv-
ative 4b would provide anti-product 2b via 3b. There-
fore, geometry-selective synthesis of the 3-alkoxy-2-
propenyl group in 4 was important for the success of
the strategy.
First, we examined the stereoselective preparation of E-
3-benzyloxy-2-propenyl glycolate 10, corresponding to
4a, and its transformation into eight-membered cyclic
ether 12 (Scheme 2). The glycolate ester 10 was prepared
by condensation reaction of glycolic acid 9 with E-3-
benzyloxy-2-propenol 88 (93%). The geometry-selective
synthesis of 8 employed Irelandꢀs procedure7g with some
modifications. Benzyl alcohol 5 reacted with methyl pro-
piolate 6 in the presence of Me3P9 to give 7 exclusively
(96%), which was reduced with DIBAH into 8 (93%).
Deprotonation of 10 with KHMDS at ꢀ78 ꢁC for
5 min followed by treatment with TMSCl and warming
to ambient temperature induced Ireland–Claisen rear-
rangement to produce a 2,3-dialkoxy-4-pentenoic acid
as a single diastereomer, which was converted with
CH2N2 to methyl ester 11 in 79% overall yield. Ring clo-
sure of 11 with first-generation Grubbsꢀ catalyst10 gave
eight-membered cyclic ether 1211 in 87% yield. The rela-
tive stereochemistry at C2 and C3 in 12 was confirmed
as (2R*,3S*) by the presence of NOE between H2 and
H3 as well as small JH2–H3 (3.3 Hz). Thus, the Ireland–
Claisen rearrangement of E-3-alkoxy-2-propenyl glyco-
late 10 gave exclusively syn-2,3-dialkoxy-4-pentenoate
11, which was smoothly cyclized into eight-membered
cyclic ether 12 by RCM.
Then, the Ireland–Claisen rearrangement of 16 and the
subsequent RCM were investigated. The ester 16 was
deprotonated with KHMDS in the presence of TMSCl
at ꢀ78 ꢁC, and the resulting ketene silyl acetal was rear-
ranged during warming to ambient temperature to pro-
duce 17 exclusively in 81% overall yield from 15. The
carboxylic acid 17 was transformed into 18 with
CH2N2 (81%). The diene 18 was cyclized with second-
generation Grubbsꢀ catalyst16 into eight-membered cyc-
lic ether 1917 in 53% yield.18 The trans-geometry of the
substituents at C2 and C3 of 19 was determined by the
large JH2–H3 (9.2 Hz) and absence of NOE between H2
and H3. Thus, the process including Ireland–Claisen
rearrangement and RCM starting from Z-3-alkoxy-2-
propenyl glycolate ester 16 efficiently completed the con-
struction of trans-disubstituted eight-membered cyclic
ether 19 stereoselectively.
Next, stereoselective synthesis of Z-3-(4-methoxyphen-
yloxy)-2-propenyl glycolate 16, corresponding to 4b,
was examined (Scheme 3). Although several methods
for preparing Z-3-alkoxy-2-propenyl alcohols were
reported,12 a more selective and simpler method was
required for our synthesis. Therefore, we investigated a

K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 3465–3468
3467
Sasaki, M.; Inoue, M.; Noguchi, T.; Takechi, A.; Tachi-
bana, K. Tetrahedron Lett. 1998, 39, 2783; (f) Crimmins,
M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653; (g)
Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.; Maeda, K.; Oguri,
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Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.; Shindo,
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(l) Fujiwara, K.; Koyama, Y.; Doi, E.; Shimawaki, K.;
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Synlett 2002, 1496; (m) Takemura, A.; Fujiwara, K.;
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45, 7567.
In conclusion, a simple stereoselective synthesis of cis-
and trans-3-alkoxy-2-carbomethoxy-2,3,6,7-tetrahydro-
oxocines has been developed based on geometry-
selective synthesis of E- and Z-3-alkoxy-2-propenyl gly-
colates, Ireland–Claisen rearrangement of the glycolate
esters, and the subsequent ring-closing olefin metathesis.
The next challenge toward the application of the method
to natural product synthesis is asymmetric induction
during the Ireland–Claisen rearrangement of the sub-
strate having a cyclic ether group on the C2-oxygen of
the glycolate part or on the C3-oxygen of the 2-propenyl
part. The solution of the challenge will provide an
efficient synthesis of a fused polycyclic ether system.
Further studies on the issue are now in progress in our
laboratory.
6. Recent reviews: (a) Castro, A. M. M. Chem. Rev. 2004,
104, 2939; (b) Nubbemeyer, U. Synthesis 2003, 961; (c)
Chai, Y.; Hong, S.-p.; Lindsay, H. A.; McFarland;
McIntosh, M. C. Tetrahedron 2002, 58, 2905; For the
tandem use of Ireland–Claisen rearrangement and ring-
closing olefin metathesis, see: (d) Miller, J. F.; Termin, A.;
Koch, K.; Piscopio, A. D. J. Org. Chem. 1998, 63, 3158;
(e) Burke, S. D.; Ng, R. A.; Morrison, J. A.; Alberti, M. J.
J. Org. Chem. 1998, 63, 3160.
7. Although the rearrangement using the substrates having
either a glycolate part or a 3-alkoxy-2-propenyl part was
already reported, there was no report about 3-alkoxy-2-
propenyl glycolate esters except glycal glycolate esters. For
glycolate esters see: (a) Whitesell, J. K.; Matthews, R. S.;
Helbling, A. M. J. Org. Chem. 1978, 43, 784; (b) Bartlett,
P. A.; Tanzella, D. J.; Barstow, J. F. J. Org. Chem. 1982,
47, 3941; (c) Sato, T.; Tajima, K.; Fujisawa, T. Tetrahe-
dron Lett. 1983, 24, 729; (d) Burke, S. D.; Fobare, W. F.;
Pacofsky, G. J. J. Org. Chem. 1983, 48, 5221; (e) Gould, T.
J.; Balestra, M.; Wittman, M. D.; Gary, J. A.; Rossano, L.
T.; Kallmerten, J. J. Org. Chem. 1987, 52, 3889; For 3-
alkoxy-2-propenyl esters, see: (f) Ireland, R. E.; Wilcox, C.
S. Tetrahedron Lett. 1977, 18, 2839; (g) Ireland, R. E.;
Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J. Org. Chem.
1980, 45, 48, For glycal glycolate esters, see Ref. 7g; (h)
Ireland, R. E.; Thaisrivongs, S.; Wilcox, C. S. J. Am.
Chem. Soc. 1980, 102, 1155; (i) Ireland, R. E.; Anderson,
R. C.; Badoud, R.; Fitzsimmons, B. J.; McGarvey, G. J.;
Thaisrivongs, S.; Wilcox, C. S. J. Am. Chem. Soc. 1983,
Acknowledgements
We thank Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC–MS & NMR Laboratory, Graduate School of
Agriculture, Hokkaido University) for the measure-
ments of mass spectra. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Culture, Sports, Science, and Technology
of Japanese Government.
References and notes
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1
11. Selected spectral data of 12: H NMR (300 MHz, CDCl3)
d 7.37–7.19 (5H, m), 6.02 (1H, ddd, J = 7.7, 8.8, 11.0 Hz),
5.71 (1H, dd, J = 7.0, 11.0 Hz), 4.98 (1H, d, J = 12.1 Hz),
4.44 (1H, dd, J = 3.3, 7.0 Hz), 4.39 (1H, d, J = 12.1 Hz),
4.19 (1H, d, J = 3.3 Hz), 4.16 (1H, td, J = 3.9, 11.7 Hz),
3.73 (3H, s), 3.54–3.41 (1H, m), 2.88–2.70 (1H, m), 2.13–
1.90 (2H, m), 1.63–1.45 (1H, m); 13C NMR (75 MHz,
CDCl3) d 170.3 (c), 138.0 (C), 135.4 (CH), 128.2 (CH · 2),
127.73 (CH · 2), 127.54 (CH), 127.43(CH), 82.0 (CH),
75.5 (CH), 70.4 (CH2 · 2), 52.1 (CH3), 30.5 (CH2), 24.5
(CH2); IR (film) mmax 3029, 2935, 1756, 1497, 1455, 1436,
1389, 1349, 1283, 1203, 1177, 1141, 1115, 1089, 1074, 1028,
736, 699 cmꢀ1; LR-FDMS, m/z 277 (22%, [M+1]+), 276
´
Martın, J. D. Chem. Rev. 1995, 95, 1953.
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Weinhem, 2003.
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Hirama, M. Synlett 1997, 980; (d) Sasaki, M.; Noguchi,
T.; Tachibana, K. Tetrahedron Lett. 1999, 40, 1337; (e)

3468
K. Fujiwara et al. / Tetrahedron Letters 46 (2005) 3465–3468
(bp, [M]+); HR-FDMS, calcd for C16H20O4 [M]+
276.1362, found: 276.1337.
:
16. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953.
1
12. (a) Wollenberg, R. H.; Albizati, K. F.; Peries, R. J. Am.
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15. The production of 4-methoxyphenyl-1-propenyl ether was
probably due to the presence of the acidic protons in 15
and/or a sulfonyl imine, resulting from the deoxygenation
of 15. The allylic anion of 13 would absorb these protons
rather than the oxygen atom of the oxaziridine in 14.
Further exploration of effective oxidants is currently
underway.
17. Selected spectral data of 19: H NMR (300 MHz, CDCl3)
d 6.79 (4H, brs), 5.83 (1H, dddd, J = 11.2, 8.3, 6.6, 2.9 Hz),
5.70 (1H, dd, J = 11.2, 6.0 Hz), 5.05 (1H, ddd, J = 9.2, 6.0,
2.9 Hz), 4.13 (1H, ddd, J = 11.0, 4.7, 4.0 Hz), 4.01 (1H, d,
J = 9.2 Hz), 3.75 (6H, s), 3.59 (1H, td, J = 11.0, 4.7 Hz),
2.52 (1H, tdd, J = 13.2, 9.9, 4.7 Hz), 2.19 (1H, dddd,
J = 13.2, 7.3, 4.0, 3.3 Hz), 2.06 (1H, ddtd, J = 13.2, 11.0,
4.7, 3.3 Hz), 1.52 (1H, tq, J = 13.2, 4.0 Hz); 13C NMR
(75 MHz, CDCl3) d 170.2 (C), 154.4 (C), 151.5 (C), 132.2
(CH), 131.3 (CH), 117.0 (CH · 2), 114.5 (CH · 2), 83.1
(CH), 76.5 (CH), 69.8 (CH2), 55.7 (CH3), 52.2 (CH3), 30.1
(CH2), 24.2 (CH2); IR (film) mmax 3024, 2951, 2836, 1750,
1506, 1464, 1436, 1284, 1227, 1170, 1117, 1035, 996, 825,
733 cmꢀ1; LR-FDMS, m/z 293 (18%, [M+1]+), 292 (bp,
[M]+); HR-FDMS, calcd for C16H20O5 [M]+ : 292.1311,
found: 292.1317.
18. When diene 18 was refluxed with first-generation Grubbsꢀ
catalyst in CH2Cl2, cyclic ether 19 was not produced and
18 was recovered almost quantitatively.